For patients with hematologic malignancies such as leukemias, lymphomas and other related cancers, allogeneic blood/marrow transplantation (allo BMT) is a critically important therapy that can produce cures when chemotherapy alone cannot. More than 25,000 patients undergo allo BMT world-wide each year. A major risk of allo BMT continues to be graft-versus-host disease (GVHD), which results from the donor immune system recognizing the transplant recipient's organs as foreign, leading to life-threatening inflammation. Developing strategies that reduce GVHD but leave global immune function intact should produce a major benefit for patients. One promising approach that we have developed is targeting the complex community of microbes that reside within our intestinal tracts, collectively termed the intestinal microbiota. While a relationship between the microbiota and GVHD has been suspected for many years, it remains imperfectly understood. Gut decontamination with antibiotics is practiced at some but not all centers, and there is no consensus regarding ideal choice of antibiotic coverage. The preliminary data in this application present a novel finding: the abundance of bacteria belonging to the genus Blautia, commonly found in the intestinal tract of humans, predicts for protection from life-threatening GVHD in allo BMT patients. Furthermore, introducing in murine models a species of Blautia of murine origin, or a mixture of Blautia and related bacteria of human origin reduces GVHD severity. A possible mechanism appears to be generation of short-chain fatty acids (SCFA), inducing donor regulatory T cells, and modulating inflammation by donor alloreactive T cells. Additional preliminary data demonstrate that a variety of microbiota-focused strategies appear to alleviate GVHD in mice. Strategies include administration to mice of a SCFA, acetate, selecting antibiotics that spare obligate anaerobes, and targeted introduction of a sugar that is fermented by Blautia. Our results have identified the microbiota as a potent ally that can be recruited to significantly redue GVHD. The project aims to study the effects of intestinal flora composition on GVHD, to evaluate strategies to treat microbiota injury and GVHD, and to develop strategies to prevent microbiota injury in allo BMT patients. The overarching goal is to lay the foundation for a multi-pronged approach to clinically translate these findings into personalized therapies for allo BMT patients that are tailored to their particular microbiota status.